Elsevier

The Lancet

Volume 350, Issue 9072, 19 July 1997, Pages 161-165
The Lancet

Articles
Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomised multicentre trial*

https://doi.org/10.1016/S0140-6736(97)06305-8Get rights and content

Summary

Background

Human tumour cells can proliferate rapidly, and giving radiotherapy in many small fractions may reduce long-term normal-tissue morbidity. In response to these observations, we developed the CHART (continuous hyperfractionated accelerated radiotherapy) regimen, which uses thirty-six small fractions of 1·5 Gy given three times per day, to give 54 Gy in only 12 consecutive days. We report the long-term follow-up of a trial of CHART versus conventional radiotherapy in patients with locally advanced non-small-cell lung cancer (NSCLC).

Methods

563 patients were entered by thirteen centres between April, 1990, and March, 1995. We included patients with NSCLC localised to the chest with a performance status of 0 or 1 in whom radical radiotherapy was chosen as the definitive management. Patients were randomly allocated in a 3:2 ratio to CHART or conventional radiotherapy. The latter was thirty fractions of 2 Gy to a total dose of 60 Gy in 6 weeks.

Results

The groups were well matched for possible prognostic factors. Overall there was a 24% reduction in the relative risk of death, which is equivalent to an absolute improvement in 2-year survival of 9% from 20% to 29% (p=0·004, 95% CI 0·63–0·92). Subgroup analyses (predefined) suggest that the largest benefit occurred in patients with squamous cell carcinomas (82% of the cases), in whom there was a 34% reduction in the relative risk of death (an absolute improvement at 2 years of 14% from 19% to 33%). During the first 3 months, severe dysphagia occurred more often in the CHART group than in the group on conventional radiotherapy (19 vs 3%). Otherwise, there were no important differences in short-term or long-term morbidity.

Interpretation

CHART compared with conventional radiotherapy gave a significant improvement in survival of patients with NSCLC. Further improvement may be achieved with dose escalation in conformal radiotherapy, by the addition of cytotoxic chemotherapy, and by hypoxic cell radiosensitisation.

Introduction

Lung cancer is the most common cause of cancer death in the developed world and the incidence is rising steeply in the developing world.1 Non-small-cell lung cancer (NSCLC) accounts for about three-quarters of all cases.2 Surgery is the most successful treatment but is only beneficial in the minority of patients with early disease.2 Radiotherapy can benefit the patient with early disease.3 Patients with advanced tumours, which are apparently localised to the chest, may be treated by radiotherapy with curative intent but the results remain unsatisfactory (survival of 40% and 15% at 1 and 2 years).4, 5, 6 Attempts have been made to improve results by combining radiation with cytotoxic chemotherapy given before, during, or after radiotherapy to enhance the local response and to eradicate occult metastases. Small benefits have been shown in some trials: a meta-analysis showed an absolute improvement in survival of 4% at 2 years.7 Despite the high frequency of distant metastases, most patients die of uncontrolled disease within the chest.8, 9 Therefore, efforts to improve primary tumour control, if successful, could prolong survival. Further, distant metastasis may follow failure to eradicate the primary tumour and so the overall frequency of metastasis might be reduced by more effective treatment to the primary site.10 Conventional radiotherapy with curative intent commonly involves a daily dose increment of 2 Gy Monday to Friday for 6 weeks to achieve a total of 60 Gy. However, human cancer cells can rapidly proliferate.11 Giving radiotherapy in many small fractions may reduce long-term normal-tissue morbidity.12 These observations led to the introduction of continuous hyperfractionated accelerated radiotherapy (CHART) at Mount Vernon Hospital in January, 1985. The overall duration was reduced from 40 to 12 days to minimise the opportunity for cell proliferation. A small dose per fraction of 1·5 Gy was used to improve tolerance and was given three times per day every day including the weekend. In a pilot study of 76 patients with NSCLC, there was improved primary tumour control and survival compared with historical controls.13 A multicentre randomised trial in NSCLC was designed in 1989 to run in parallel with a similar study in head and neck cancer. In both, the CHART regimen was compared with conventional radiotherapy. A 3:2 randomisation in favour of CHART facilitated the giving of CHART to groups of patients. Endpoints were survival, disease-free interval, local tumour control, and morbidity. An interim report on both trials was prepared immediately after closure of entry in April, 1995.14 Here we report the definitive results of the trial in NSCLC.

Section snippets

Design and eligibility

This was a multicentre randomised comparison of CHART versus conventional radiotherapy in patients with NSCLC (figure 1). Eligible patients were those with pathologically proven, inoperable NSCLC with a WHO performance status of 0 or 1 who were suitable for radical radiotherapy.

Radiotherapy

The planning process was identical for all patients regardless of the treatment allocated. The course of treatment was divided into two phases. During the first, “a large volume” was irradiated which included the

Morbidity due to treatment during the initial 3 months

Morbidity during treatment was confined to dysphagia which occurred sooner and was severer in the CHART patients, of whom 19% were reduced to fluids only or were classified as having severe difficulty compared with 3% of conventionally treated cases (figure 3). Dysphagia settled satisfactorily in patients in both arms of the study; at 3 months, 9% of the CHART patients and 7% of the conventional cases were reported to have some persistent dysphagia due to treatment but this was usually slight.

Intermediate morbidity

Paraesthesia in the lower limbs on neck flexion (Lhermittes sign21) was recorded at one follow-up in eight patients, all treated with CHART. In these patients, Lhermittes occurred 3–16 months after treatment with a mean time of occurrence of 9·1 months. In later follow-up which ranged from 3 to 19 months, no further neurological symptoms were recorded.

Late morbidity

A clinical assessment of symptoms considered due to pulmonary fibrosis after radiation was made at each follow-up. Of those alive at 2 years, 16% of those treated with CHART and 4% treated conventionally had pulmonary fibrosis that required outpatient treatment. Similarly, radiation changes were assessed radiographically; at 2 years 45% of the CHART cases and 48% of those conventionally treated showed moderate or severe changes in the treatment volume. A small number of patients also reported

Cause of death

444 patients have now died and a similar distribution of cause was observed in both arms of the trial. The primary tumour was the principal cause of death in 61% of the CHART cases and in 60% of those treated conventionally. There were six cases in which the principal cause of death was considered to be radiation morbidity-three in each arm of the study-and all were related to changes in the lung secondary to treatment.

Discussion

We have shown that CHART improved survival compared with conventional radiotherapy for patients with locally advanced NSCLC. There was evidence that the largest benefit was gained by patients with squamous cell carcinoma. The survival improvement we saw can be compared with that reported in the meta-analysis of randomised controlled trials of chemotherapy in NSCLC.7 That meta-analysis of over 3000 cases entered into twenty-two trials of chemotherapy added to radiation showed a 13% reduction in

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